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Gene and Cell Therapy in Regenerative Medicine—Second Edition

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: 10 June 2024 | Viewed by 8899

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Special Issue Editors

Prof. Dr. Albert Rizvanov

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Guest Editor

Institute of Fundamental Medicine and Biology, Department of Genetics, Kazan Federal University, Kazan, Russia
Interests: multi-omics medicine; precision medicine; regenerative medicine; gene and cell therapy; molecular neurobiology; molecular virology; cancer diagnostics and therapy
Special Issues, Collections and Topics in MDPI journals

Dr. Ayşegül Doğan

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Guest Editor

Department of Genetics and Bioengineering, T.C. Yeditepe Universitesi, Istanbul, Turkey
Interests: pluripotent stem cells; organoids; gene editing; neuromesodermal progenitors; apelin signalling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This is the expanded second edition of our previous Special Issue, “Gene and Cell Therapy in Regenerative Medicine”, the first edition of which published 10 papers.

Despite recent advances in biomedical and clinical research, many diseases and conditions still lack effective treatments, resulting in inadequate recovery and a poor quality of life for patients. Gene and cell therapy represent a promising approach to overcoming the natural restrictions of the body relating to regeneration. This approach can be used to eliminate the cause of the disease or condition, such as through the correction of genetic mutations and hereditary factors. Another approach is based on cell replacement strategies designed to compensate for the lack of, or increase in, the pool of certain cells. A further approach is based on the paracrine theory behind regeneration, where gene therapy or transplanted cells result in the secretion of different growth factors, other biological molecules such as proteins, metabolites, RNA, and others, and microvesicles, which are able to stimulate angiogenesis, neuroprotection/neuroregeneration, osteo- and/or chondrogenesis, as well as other regenerative processes. Finally, to further increase the efficiency of regenerative treatments, and to overcome problems related to the targeted delivery of gene therapy in vivo, combination gene–cell therapy can be used to correct genetic mutations ex vivo, achieve transgene expression or use cells as delivery systems for the gene therapy targeted delivery.

Potential topics include, but are not limited to, the following:

Isolation, expansion and analysis of stem cells from various tissues and organs for biomedical and clinical applications;
Applications of autologous and allogeneic natural and genetically modified cells;
Stem cells in tissue engineering (3D printing, organoids, decellularized tissues and organs, natural and artificial matrixes, etc.);
Immunomodulatory effects of stem cells;
Gene therapy (vector development, therapeutic gene editing, transgene delivery, etc.);
Using genetic modification and chemical treatments for modulating biological properties and therapeutic efficiency of stem and differentiated;
Characterization and application of natural and artificial membrane vesicles from various natural and genetically modified cells for regenerative medicine.

Prof. Dr. Albert Rizvanov
Dr. Ayşegül Doğan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

gene therapy
cell therapy
regenerative medicine
growth factors
stem cells

Published Papers (7 papers)

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Research

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13 pages, 2979 KiB

Open AccessArticle

Comparison of Minced Cartilage Implantation with Autologous Chondrocyte Transplantation in an In Vitro Inflammation Model

by Robert Ossendorff, Lisa Grede, Sebastian Scheidt, Andreas C. Strauss, Christof Burger, Dieter C. Wirtz, Gian M. Salzmann and Frank A. Schildberg

Cells 2024, 13(6), 546; https://doi.org/10.3390/cells13060546 - 20 Mar 2024

Viewed by 806

Abstract

The current gold standard to treat large cartilage defects is autologous chondrocyte transplantation (ACT). As a new surgical method of cartilage regeneration, minced cartilage implantation (MCI) is increasingly coming into focus. The aim of this study is to investigate the influence of chondrogenesis between isolated and cultured chondrocytes compared to cartilage chips in a standardized inflammation model with the proinflammatory cytokine TNFα. Articular chondrocytes from bovine cartilage were cultured according to the ACT method to passage 3 and transferred to spheroid culture. At the same time, cartilage was fragmented (<1 mm³) to produce cartilage chips. TNFα (20 ng/mL) was supplemented to simulate an inflammatory process. TNFα had a stronger influence on the passaged chondrocytes compared to the non-passaged ones, affecting gene expression profiles differently between isolated chondrocytes and cartilage chips. MCI showed less susceptibility to TNFα, with reduced IL-6 release and less impact on inflammation markers. Biochemical and histological analyses supported these findings, showing a greater negative influence of TNFα on the passaged pellet cultures compared to the unpassaged cells and MCI constructs. This study demonstrated the negative influence of TNFα on chondrogenesis in a chondrocyte spheroid culture and cartilage fragment model. Passaged chondrocytes are more sensitive to cytokine influences compared to non-passaged cells and chondrons. This suggests that MCI may have superior regeneration potential in osteoarthritic conditions compared to ACT. Further investigations are necessary for the translation of these findings into clinical practice. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)

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21 pages, 3037 KiB

Open AccessArticle

The Combination of Vascular Endothelial Growth Factor A (VEGF-A) and Fibroblast Growth Factor 1 (FGF1) Modified mRNA Improves Wound Healing in Diabetic Mice: An Ex Vivo and In Vivo Investigation

by Sandra Tejedor, Maria Wågberg, Cláudia Correia, Karin Åvall, Mikko Hölttä, Leif Hultin, Michael Lerche, Nigel Davies, Nils Bergenhem, Arjan Snijder, Tom Marlow, Pierre Dönnes, Regina Fritsche-Danielson, Jane Synnergren, Karin Jennbacken and Kenny Hansson

Cells 2024, 13(5), 414; https://doi.org/10.3390/cells13050414 - 27 Feb 2024

Viewed by 1410

Abstract

Background: Diabetic foot ulcers (DFU) pose a significant health risk in diabetic patients, with insufficient revascularization during wound healing being the primary cause. This study aimed to assess microvessel sprouting and wound healing capabilities using vascular endothelial growth factor (VEGF-A) and a modified fibroblast growth factor (FGF1). Methods: An ex vivo aortic ring rodent model and an in vivo wound healing model in diabetic mice were employed to evaluate the microvessel sprouting and wound healing capabilities of VEGF-A and a modified FGF1 both as monotherapies and in combination. Results: The combination of VEGF-A and FGF1 demonstrated increased vascular sprouting in the ex vivo mouse aortic ring model, and topical administration of a combination of VEGF-A and FGF1 mRNAs formulated in lipid nanoparticles (LNPs) in mouse skin wounds promoted faster wound closure and increased neovascularization seven days post-surgical wound creation. RNA-sequencing analysis of skin samples at day three post-wound creation revealed a strong transcriptional response of the wound healing process, with the combined treatment showing significant enrichment of genes linked to skin growth. Conclusion: f-LNPs encapsulating VEGF-A and FGF1 mRNAs present a promising approach to improving the scarring process in DFU. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)

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26 pages, 5485 KiB

Open AccessArticle

Adipose Stromal Cell-Derived Secretome Attenuates Cisplatin-Induced Injury In Vitro Surpassing the Intricate Interplay between Proximal Tubular Epithelial Cells and Macrophages

by Erika Rendra, Stefanie Uhlig, Isabell Moskal, Corinna Thielemann, Harald Klüter and Karen Bieback

Cells 2024, 13(2), 121; https://doi.org/10.3390/cells13020121 - 9 Jan 2024

Cited by 1 | Viewed by 1000

Abstract

(1) Background: The chemotherapeutic drug cisplatin exerts toxic side effects causing acute kidney injury. Mesenchymal stromal cells can ameliorate cisplatin-induced kidney injury. We hypothesize that the MSC secretome orchestrates the vicious cycle of injury and inflammation by acting on proximal tubule epithelial cells (PTECs) and macrophages individually, but further by counteracting their cellular crosstalk. (2) Methods: Conditioned medium (CM) from adipose stromal cells was used, first assessing its effect on cisplatin injury in PTECs. Second, the effects of cisplatin and the CM on macrophages were measured. Lastly, in an indirect co-culture system, the interplay between the two cell types was assessed. (3) Results: First, the CM rescued PTECs from cisplatin-induced apoptosis by reducing oxidative stress and expression of nephrotoxicity genes. Second, while cisplatin exerted only minor effects on macrophages, the CM skewed macrophage phenotypes to the anti-inflammatory M2-like phenotype and increased phagocytosis. Finally, in the co-culture system, the CM suppressed PTEC death by inhibiting apoptosis and nuclei fragmentation. The CM lowered TNF-α release, while cisplatin inhibited macrophage phagocytosis, PTECs, and the CM to a greater extent, thus enhancing it. The CM strongly dampened the inflammatory macrophage cytokine secretion triggered by PTECs. (4) Conclusions: ASC-CM surpasses the PTEC–macrophage crosstalk in cisplatin injury. The positive effects on reducing cisplatin cytotoxicity, on polarizing macrophages, and on fine-tuning cytokine secretion underscore MSCs’ CM benefit to prevent kidney injury progression. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)

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24 pages, 4763 KiB

Open AccessArticle

Evaluation of Mono- and Bi-Functional GLOBE-Based Vectors for Therapy of β-Thalassemia by HBB^AS3 Gene Addition and Mutation-Specific RNA Interference

by Lola Koniali, Christina Flouri, Markela I. Kostopoulou, Nikoletta Y. Papaioannou, Panayiota L. Papasavva, Basma Naiisseh, Coralea Stephanou, Anthi Demetriadou, Maria Sitarou, Soteroula Christou, Michael N. Antoniou, Marina Kleanthous, Petros Patsali and Carsten W. Lederer

Cells 2023, 12(24), 2848; https://doi.org/10.3390/cells12242848 - 15 Dec 2023

Viewed by 1182

Abstract

Therapy via the gene addition of the anti-sickling β^AS3-globin transgene is potentially curative for all β-hemoglobinopathies and therefore of particular clinical and commercial interest. This study investigates GLOBE-based lentiviral vectors (LVs) for β^AS3-globin addition and evaluates strategies for an increased β-like globin expression without vector dose escalation. First, we report the development of a GLOBE-derived LV, GLV2-βAS3, which, compared to its parental vector, adds anti-sickling action and a transcription-enhancing 848-bp transcription terminator element, retains high vector titers and allows for superior β-like globin expression in primary patient-derived hematopoietic stem and progenitor cells (HSPCs). Second, prompted by our previous correction of HBB^{IVSI−110(G>A)} thalassemia based on RNApol(III)-driven shRNAs in mono- and combination therapy, we analyzed a series of novel LVs for the RNApol(II)-driven constitutive or late-erythroid expression of HBB^{IVSI−110(G>A)}-specific miRNA30-embedded shRNAs (shRNAmiR). This included bifunctional LVs, allowing for concurrent β^AS3-globin expression. LVs were initially compared for their ability to achieve high β-like globin expression in HBB^{IVSI−110(G>A)}-transgenic cells, before the evaluation of shortlisted candidate LVs in HBB^{IVSI−110(G>A)}-homozygous HSPCs. The latter revealed that β-globin promoter-driven designs for monotherapy with HBB^{IVSI−110(G>A)}-specific shRNAmiRs only marginally increased β-globin levels compared to untransduced cells, whereas bifunctional LVs combining miR30-shRNA with β^AS3-globin expression showed disease correction similar to that achieved by the parental GLV2-βAS3 vector. Our results establish the feasibility of high titers for LVs containing the full HBB transcription terminator, emphasize the importance of the HBB terminator for the high-level expression of HBB-like transgenes, qualify the therapeutic utility of late-erythroid HBB^{IVSI−110(G>A)}-specific miR30-shRNA expression and highlight the exceptional potential of GLV2-βAS3 for the treatment of severe β-hemoglobinopathies. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)

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24 pages, 67178 KiB

Open AccessArticle

Ultrastructural Abnormalities in Induced Pluripotent Stem Cell-Derived Neural Stem Cells and Neurons of Two Cohen Syndrome Patients

by Tatiana A. Shnaider, Anna A. Khabarova, Ksenia N. Morozova, Anastasia M. Yunusova, Sophia A. Yakovleva, Anastasia S. Chvileva, Ekaterina R. Wolf, Elena V. Kiseleva, Elena V. Grigor’eva, Viktori Y. Voinova, Maria A. Lagarkova, Ekaterina A. Pomerantseva, Elizaveta V. Musatova, Alexander V. Smirnov, Anna V. Smirnova, Diana S. Stoklitskaya, Tatiana I. Arefieva, Daria A. Larina, Tatiana V. Nikitina and Inna E. Pristyazhnyuk

Cells 2023, 12(23), 2702; https://doi.org/10.3390/cells12232702 - 25 Nov 2023

Viewed by 1331

Abstract

Cohen syndrome is an autosomal recessive disorder caused by VPS13B (COH1) gene mutations. This syndrome is significantly underdiagnosed and is characterized by intellectual disability, microcephaly, autistic symptoms, hypotension, myopia, retinal dystrophy, neutropenia, and obesity. VPS13B regulates intracellular membrane transport and supports the Golgi apparatus structure, which is critical for neuron formation. We generated induced pluripotent stem cells from two patients with pronounced manifestations of Cohen syndrome and differentiated them into neural stem cells and neurons. Using transmission electron microscopy, we documented multiple new ultrastructural changes associated with Cohen syndrome in the neuronal cells. We discovered considerable disturbances in the structure of some organelles: Golgi apparatus fragmentation and swelling, endoplasmic reticulum structural reorganization, mitochondrial defects, and the accumulation of large autophagosomes with undigested contents. These abnormalities underline the ultrastructural similarity of Cohen syndrome to many neurodegenerative diseases. The cell models that we developed based on patient-specific induced pluripotent stem cells can serve to uncover not only neurodegenerative processes, but the causes of intellectual disability in general. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)

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Review

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15 pages, 658 KiB

Open AccessReview

NF-κB and JAK/STAT Signaling Pathways as Crucial Regulators of Neuroinflammation and Astrocyte Modulation in Spinal Cord Injury

by Tatyana Ageeva, Albert Rizvanov and Yana Mukhamedshina

Cells 2024, 13(7), 581; https://doi.org/10.3390/cells13070581 - 26 Mar 2024

Viewed by 799

Abstract

Spinal cord injury (SCI) leads to significant functional impairments below the level of the injury, and astrocytes play a crucial role in the pathophysiology of SCI. Astrocytes undergo changes and form a glial scar after SCI, which has traditionally been viewed as a barrier to axonal regeneration and functional recovery. Astrocytes activate intracellular signaling pathways, including nuclear factor κB (NF-κB) and Janus kinase-signal transducers and activators of transcription (JAK/STAT), in response to external stimuli. NF-κB and STAT3 are transcription factors that play a pivotal role in initiating gene expression related to astrogliosis. The JAK/STAT signaling pathway is essential for managing secondary damage and facilitating recovery processes post-SCI: inflammation, glial scar formation, and astrocyte survival. NF-κB activation in astrocytes leads to the production of pro-inflammatory factors by astrocytes. NF-κB and STAT3 signaling pathways are interconnected: NF-κB activation in astrocytes leads to the release of interleukin-6 (IL-6), which interacts with the IL-6 receptor and initiates STAT3 activation. By modulating astrocyte responses, these pathways offer promising avenues for enhancing recovery outcomes, illustrating the crucial need for further investigation into their mechanisms and therapeutic applications in SCI treatment. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)

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38 pages, 2180 KiB

Open AccessReview

Beyond Vision: An Overview of Regenerative Medicine and Its Current Applications in Ophthalmological Care

by Francisco J. Santa Cruz-Pavlovich, Andres J. Bolaños-Chang, Ximena I. Del Rio-Murillo, Guillermo A. Aranda-Preciado, Esmeralda M. Razura-Ruiz, Arturo Santos and Jose Navarro-Partida

Cells 2024, 13(2), 179; https://doi.org/10.3390/cells13020179 - 17 Jan 2024

Viewed by 1849

Abstract

Regenerative medicine (RM) has emerged as a promising and revolutionary solution to address a range of unmet needs in healthcare, including ophthalmology. Moreover, RM takes advantage of the body’s innate ability to repair and replace pathologically affected tissues. On the other hand, despite its immense promise, RM faces challenges such as ethical concerns, host-related immune responses, and the need for additional scientific validation, among others. The primary aim of this review is to present a high-level overview of current strategies in the domain of RM (cell therapy, exosomes, scaffolds, in vivo reprogramming, organoids, and interspecies chimerism), centering around the field of ophthalmology. A search conducted on clinicaltrials.gov unveiled a total of at least 209 interventional trials related to RM within the ophthalmological field. Among these trials, there were numerous early-phase studies, including phase I, I/II, II, II/III, and III trials. Many of these studies demonstrate potential in addressing previously challenging and degenerative eye conditions, spanning from posterior segment pathologies like Age-related Macular Degeneration and Retinitis Pigmentosa to anterior structure diseases such as Dry Eye Disease and Limbal Stem Cell Deficiency. Notably, these therapeutic approaches offer tailored solutions specific to the underlying causes of each pathology, thus allowing for the hopeful possibility of bringing forth a treatment for ocular diseases that previously seemed incurable and significantly enhancing patients’ quality of life. As advancements in research and technology continue to unfold, future objectives should focus on ensuring the safety and prolonged viability of transplanted cells, devising efficient delivery techniques, etc. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)

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